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      Binary surrogate endpoints in clinical trials from the perspective of case definitions

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          Abstract

          Introduction

          Surrogate endpoints are widely used in clinical trials, especially in situations where the endpoint of interest is not directly observable or to avoid long trial periods. A typical example for this case is frequently found in clinical trials in oncology, where overall survival (OS) as endpoint of interest and progression free survival (PFS) as surrogate endpoint are discriminated.

          Methods

          Based on the perspective of case definitions on surrogate endpoints, we provide a formal definition of such endpoints followed by a description of the structure of surrogate endpoints.

          Results

          Surrogate endpoints can be considered as case definitions for the endpoint of interest. Therefore, the performance of surrogate endpoints can be described using the classical terminology of diagnostic tests including sensitivity and specificity. Since such endpoints always focus on sensitivity with necessarily reduced specificity, efficacy estimates based on such endpoints are in general biased.

          Conclusion

          The abovementioned has to be taken into account while interpreting the results of clinical trials and should not be ignored while planning or conducting a study.

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          Most cited references13

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          Surrogate end points in clinical trials: are we being misled?

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            Estimating prevalence from the results of a screening test.

            This paper deals with some basis properties of screening tests. Such tests purport to separate people with disease from people without. Minimal criteria for such a process to be a test are discussed. Various ways of judging the goodness of a test are examined. A common use of tests is to estimate prevalence of disease; frequency of positive tests is shown to be a bad estimate, and the necessary adjustmants are given.
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              Surrogate endpoints in clinical trials: definition and operational criteria.

              I discuss the idea of using surrogate endpoints in the context of clinical trials to compare two or more treatments or interventions in respect to some 'true' endpoint, typically a disease occurrence. In order that treatment comparison based on a surrogate response variable have a meaningful implication for the corresponding true endpoint treatment comparison, a rather restrictive criterion is proposed for use of the adjective 'surrogate'. Specifically, I propose that a surrogate for a true endpoint yield a valid test of the null hypothesis of no association between treatment and the true response. This criterion essentially requires the surrogate variable to 'capture' any relationship between the treatment and the true endpoint, a notion that can be operationalized by requiring the true endpoint rate at any follow-up time to be independent of treatment, given the preceding history of the surrogate variable. I then discuss this operational criterion in the examples of the accompanying papers and in the setting of trials aimed at the primary and secondary prevention of cancer.
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                Author and article information

                Journal
                Eur J Microbiol Immunol (Bp)
                Eur J Microbiol Immunol (Bp)
                EUJMI
                European Journal of Microbiology & Immunology
                Akadémiai Kiadó (Budapest )
                2062-509X
                2062-8633
                04 March 2021
                31 March 2021
                : 11
                : 1
                : 18-22
                Affiliations
                [1 ] Institute for Medical Microbiology, Virology and Hygiene, University Medicine Rostock , Rostock, Germany
                [2 ] Institute of Microbiology, Infectious Diseases and Immunology, Charité – University Medicine Berlin , Berlin, Germany
                [3 ] Department of Microbiology and Hospital Hygiene, Bundeswehr Hospital Hamburg , 20359 Hamburg, Germany
                Author notes
                *Corresponding author. E-mail: philipp.warnke@ 123456med.uni-rostock.de

                Hagen Frickmann and Philipp Warnke contributed equally.

                Article
                10.1556/1886.2020.00031
                8042653
                33666567
                8495277d-847d-4302-88f2-fa81d1277c21
                © 2020, The Author(s)

                Open Access. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and reproduction in any medium for non-commercial purposes, provided the original author and source are credited, a link to the CC License is provided, and changes - if any – are indicated.

                Page count
                Figures: 1, Tables: 0, Equations: 11, References: 14, Pages: 5
                Categories
                Original Research Paper

                surrogate endpoints,bias,clinical trial,case definition
                surrogate endpoints, bias, clinical trial, case definition

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